The objective of this proposal is to test the hypothesis that the pharmacological actions of delta 1-tetrahydrocannabinol (THC) are at least in part expressed through alterations in cyclic nucleotide metabolism in the target cell. We have shown that THC antagonizes the elevation of cyclic AMP levels by prostaglandin E1 (PGE1) in cultured WI-38 fibroblasts. We propose to study the mechanism of this effect as well as possible interactions of THC and its analogs and derivatives with all known components of the cyclic nucleotide system, including hormonal elevations of cellular cyclic AMP and cyclic GMP, adenyl cyclase, cyclic nucleotide phosphodiesterase and protein kinase enzymes, and the release of cyclic nucleotides to the incubation medium. On the basis of these characterization and mechanistic studies, we will extend the investigations to other cell types, includng SV40-transformed fibroblasts, cultured neural (astrocytoma) cells and isolated liver cells, which have differing hormonal-cyclic nucleotide response profiles. BIBLIOGRAPHIC REFERENCES: McGuire, R.F. and Barber, R. Hormone Receptor Mobility and Catecholamine Binding in Membranes. J. Supramol. Struct. 4, 259, 219 (1976). Lutz, H.U., Barber, R., and McGuire, R.F. Glycoprotein-enriched Vesicles from Sheep Erythrocyte Ghosts Obtained by Spontaneous Vesiculation. J. Biol. Chem., 251, 3500 (1976).